Post-traumatic stress disorder (PTSD) is a disabling anxiety disorder resulting from exposure to traumatic events. Individuals with PTSD display elevated fear related to the trauma, marked by vivid dreams and memories of the traumatic event and avoidance of situations that serve as reminders of the event. This sensitized fear is often resistant to treatment efforts to extinguish the fear response. Exposure to chronic stress, prior to the PTSD-inducing trauma, serves as a risk factor for the development of PTSD, possibly by altering neurochemical processes related to cognition and affect. The neurotransmitter norepinephrine (NE) is involved in the stress response and has been implicated in the cognitive and affective changes seen in individuals with PTSD. In animal models, learning and retention of fear and fear extinction both involve noradrenergic signaling in the amygdala and the medial prefrontal cortex (mPFC), respectively. Furthermore, these models have been shown to be sensitive to chronic stress, with stressed animals displaying enhanced fear learning and impaired extinction learning. In the proposed experiments, the modulating effects of NE in the mPFC during fear extinction and retention will be examined first in naive rats, then in chronically stressed rats. Specifically, the release of NE in the mPFC will be examined using microdialysis during fear extinction and retention. Then, the potential for recruitment of NE to enhance fear extinction learning will be determined by elevating extracellular levels of NE prior to extinction training. Then, the involvement of post- synaptic 11- and 2-adrenoceptors in the modulatory role of NE in the mPFC during extinction will be assessed. Finally, the effects of chronic stress on the modulatory influence of NE on fear extinction and retention will be examined. These studies will elucidate the role of NE in the learning and retention of fear extinction, and in the stress-induced impairments in this learning. By understanding the mechanisms behind fear learning and extinction and the detrimental effects of chronic stress, we may begin to reveal potential therapeutic interventions for disorders involving extinction impairments, such as PTSD. PUBLIC HEALTH RELEVANCE: Post-traumatic stress disorder (PTSD) is a disabling fear-related disorder with approximately 1/3 of individuals becoming treatment resistant and developing chronic symptoms lasting 10 years or more (Kessler et al., 1995). The inability to extinguish conditioned fear is a hallmark of PTSD. Using an animal model of conditioned fear and extinction, this proposal is designed to examine potential mechanisms behind this treatment resistance. By understanding these mechanisms, we may be better able to develop therapeutic interventions for chronic PTSD sufferers.